Project Summary/Abstract The goal of this project is to develop a unified, asymmetric route to several akuammiline alkaloids. The akuammiline alkaloids are a family of indole alkaloids that have garnered attention from the synthetic community for both their complex structures and their intriguing biological activities. Members of the family have been shown to hold potential for treating cancer, pain, inflammation, diabetes, depression, and herpes simplex virus. The proposed routes should allow access to a variety of the core structures of the akuammilines, through the exploration of challenging synthetic transformations. I expect to accomplish the synthetic studies via the completion of two aims. First, I will use the unified route to access both (?)-picrinine and (?)-11-methoxyvincorine. The former of these should be accessible using a challenging, late stage oxidation. Following the synthesis of (?)-picrinine, I will explore and optimize an unusual structural rearrangement from (?)-picrinine to allow access to (?)-11-methoxyvincorine. With flexible access to those two natural products, I then propose to broaden the scope of the Fischer indolization methodology by using it to access compounds with vicinal quaternary centers. The introduction of vicinal quaternary stereocenters remains a formidable challenge in chemical synthesis. With that methodology in hand, I will use it to complete the first total synthesis of (?)-picraline, a compound which has derivatives that show promise for the treatment of type 2 diabetes. Finally, I propose to use this methodology to access (?)-(?)-akuammigine, arguably the most complex akuammiline alkaloid isolated to date. Additionally, all compounds made during the course of my research will be submitted for biological testing.